The alterations in neuroplasticity following drug abuse are believed to underlie the emergence of addiction, a devastating illness that affects millions worldwide. Despite intensive research into the mechanisms underlying addiction, the development of successful treatment options remains largely unfulfilled. It is now evident that disruptions in the circadian system, which coordinates the thousands of biological rhythms necessary for optimal functioning, is an underlying causative factor for psychiatric disease, including major depressive disorder, bipolar disorder and drug addiction. Indeed, circadian rhythms in drug sensitivity, seasonal patterns of drug use and overdose, and the susceptibility to addiction associated with genetic disruptions in the circadian system suggest a link between these systems. However, it is unclear how the molecular mechanisms that constitute the circadian clock impact reward circuitry central to drug dependence. Additionally, the lack of animal models that reliably capitulate the complexity of psychiatric disorders has limited our understanding of the underlying mechanisms of these illnesses. Our lab has identified and characterized a role for the circadian gene, Clock, in the regulation of reward circuitry and represents a promising candidate target for ameliorating critical risk factors in models of addiction and bipolar disorder. Transgenic mice with a dominant negative point mutation in this gene, Clock19, exhibit increased dopaminergic neuronal firing, upregulated TH in the VTA, increased dopaminergic tone in the NAcc and precipitates the heightened sensitivity to rewarding stimuli, including ICSS, morphine and cocaine observed in these animals. Determining the precise regulatory mechanisms by which Clock impacts reward circuitry will uncover novel therapeutic targets for the treatment of these disorders. A likely target of CLOCK in the VTA is the phosphoactive CRE-element binding protein (pCREB), the principle driver of TH transcription and is widely implicated in mediating the neuronal plasticity associated with addiction. Our lab has recently uncovered an interaction between CLOCK and pCREB at the TH promoter in the VTA providing a potential molecular link by which CLOCK regulates dopaminergic transmission and underlies the heightened dopaminergic and behavioral response to drugs of abuse in the Clock19mutant mouse. This proposal will 1) determine how CLOCK and pCREB interact at the TH promoter to drive rhythmic dopamine transcription 2) uncover the mechanisms underlying the inability of CLOCK19 to regulate dopamine transmission in the VTA and 3) determine the role of CREB signaling in Clock19 mice underlying the heightened sensitivity to cocaine in this model of bipolar mania. Together, these studies will bridge the gap between the circadian system and reward circuitry implicated in the development of drug dependence associated with multiple psychiatric diseases. PUBLIC HEALTH RELEVANCE: Many psychiatric illnesses, including drug addiction, are associated with disturbances in the circadian system. It is clear that these disturbances represent a potential cause, rather than a symptom of these illnesses. This connection remains correlative, as the mechanisms underlying the circadian control of reward circuitry are largely unexplored. The McClung lab has characterized a suite of neurobiolgical and behavioral alterations associated with increased dopaminergic firing and TH levels and heightened sensitivity to drugs of abuse in animals with a dominant mutation in the circadian Clock gene (Clock19). Determining the precise regulatory mechanisms by which Clock impacts reward circuitry will uncover novel therapeutic targets for the treatment of these disorders. These experiments aim to uncover the mechanisms by which CLOCK regulates TH in the VTA, and how the Clock19 mutation results in the dopaminergic upregulation central to the increased drug seeking in this model of bipolar mania, thus bridging the gap between the circadian system and reward circuitry implicated in the development of drug dependence.